Ophthalmic composition

ABSTRACT

The present invention relates to ophthalmic compositions for treatment of conditions in the eye. More specifically, the present invention relates to ophthalmic compositions comprising a polyquaternium compound and an anionic polymer. Methods for reducing and/or preventing the incompatibility of polyquaternium compounds with anionic polymers are also disclosed.

FIELD OF THE INVENTION

The present invention relates to ophthalmic compositions for treatmentof conditions in the eye. More specifically, the present inventionrelates to ophthalmic compositions comprising a polyquaternium compoundand an anionic polymer. Methods for reducing and/or preventing theincompatibility of polyquaternium compounds with anionic polymers arealso disclosed.

BACKGROUND OF THE INVENTION

Ophthalmic solutions are sterile solutions, free from foreign particles,for instillation into the eye. In some uses, they do not havemedications in them and are only lubricating and tear-replacingsolutions or eye washes. In other uses, they have active ingredients inthem and can be used to treat such conditions as dry eye, allergies, eyeinfections such as pink eye or conjunctivitis, or eye conditions such asglaucoma. They can also be used by opticians as mydriatic compositionsto dilate the pupils of patients during eye examinations.

Anionic polymers such as hyaluronic acid and carboxyl vinyl polymershave been found useful in ophthalmic solutions for the treatment of eyeconditions such as dry eye.

To avoid introducing infective agents into the eye, it is critical thatophthalmic solutions remain sterile in their storage containers betweenuses. Polyquaternium compounds are polycationic polymers that are usedas surfactants in the personal care industry. Some have antimicrobialproperties, and can find use as a preservative in contact lenssolutions.

An issue with polyquaternium compounds is their tendency to react withanionic materials. In eye care solutions containing anionic polymers,attempts to increase the concentration of polyquaternium in thecompositions results in the formation of a precipitate. The precipitateis believed to be the complexation product of anionic polymer and thepolyquaternium.

There is, therefore, a need for compositions containing polyquaterniumcompounds with anionic polymers having reduced precipitate formation orcomplexation.

The present inventors have found that an amount of an organic acideffective for binding with the polyquaternium in at least a 1:1 molarratio to inhibit, reduce or prevent the precipitation and/orcomplexation of the polyquaternium compound and the anionic polymer.

It is therefore an aspect of the present invention to providecompositions comprising a polyquaternium compound and an anionic polymerwherein the precipitation or complexation of the polyquaternium compoundand an anionic polymer is reduced or prevented.

A further aspect of the present invention relates to compositioncomprising a polyquaternium compound, an anionic polymer and aneffective amount of an organic acid such that precipitation and/orcomplexation of the polyquaternium compound and an anionic polymer isinhibited, reduced or prevented.

SUMMARY OF THE INVENTION

The present invention is directed to ophthalmic compositions fortreatment of conditions in the eye. In one embodiment, the compositioncomprises from 10 ppm (or about 10 ppm) to 1000 ppm (or about 1000 ppm)of a polyquaternium having a weight average molecular weight of fromabout 150 to about 15,000 Daltons, from 0.001% (or about 0.001%) to 0.5%(or about 0.5%) of an anionic polymer having a weight average molecularweight of from about 250 Daltons to about 4,000,000 Daltons, and aneffective amount of an organic acid, salts thereof or mixtures thereof,for binding with the polyquaternium in at least a 1:1 molar ratio,where, in certain embodiments, the composition is substantially free ofcationic oligomer compounds and/or precipitation inhibiting compoundssuch as amphoteric surfactants having a weight average molecular weightof greater than about 303.4 Daltons.

The present invention further relates to a method of reducing,inhibiting or preventing the precipitation of a polyquaternium compoundand an anionic polymer in a composition comprising such compounds,comprising the steps of:

-   -   i) providing from about 0.001% to about 0.5% of an anionic        polymer having a weight average molecular weight of from about        250 to about 4,000,000 Daltons;    -   ii) adding an effective amount of an organic acid, salts thereof        or mixtures thereof, such that the organic acid binds with the        polyquaternium compound in at least a 1:1 molar ratio    -   iii) adding from about 10 ppm to about 1000 ppm of a        polyquaternium compound having a weight average molecular weight        of from about 150 to about 15,000 Daltons;        wherein the composition is substantially free of cationic        oligomer compounds and precipitation inhibiting compounds.

DETAILED DESCRIPTION OF THE INVENTION

As indicated above, the present invention relates to ophthalmiccompositions comprising an anionic polymer such as hyaluronic acid (HA)preserved with a polyquaternium compound such as polyquaternium-42wherein precipitate formation or complexation of the anionic polymer andpolyquaternium compound is reduced and/or prevented.

The compositions and methods of the present invention can comprise,consist of, or consist essentially of the steps, essential elements andlimitations of the invention described herein, as well any of theadditional or optional ingredients, components, or limitations describedherein. The term “comprising” (and its grammatical variations) as usedherein is used in the inclusive sense of “having” or “including” and notin the exclusive sense of “consisting only of.” The terms “a” and “the”as used herein are understood to encompass the plural as well as thesingular.

Unless otherwise indicated, all documents cited are, in relevant part,incorporated herein by reference; the citation of any document is not tobe construed as an admission that it is prior art with response to thepresent invention. Furthermore, all documents incorporated herein byreference are only incorporated herein to the extent that they are notinconsistent with this specification.

The term “effective amount” means that amount of the organic acidnecessary to achieve complete association of the organic acid with thepolyquaternium compound such that the molar ratio of the organic acidwith the polyquaternium compound is at least 1:1.

The term “clear” means the absence of cloudiness and/or particles uponvisual inspection.

As used herein, the term “visual inspection” means that a human viewercan visually discern the presence of particles or cloudiness with theunaided eye (excepting standard corrective lenses adapted to compensatefor near-sightedness, farsightedness, or stigmatism, or other correctedvision) in lighting at least equal to the illumination of a standard 75watt incandescent white light bulb at a distance of about 0.25 meter.

In certain embodiments, the present invention as disclosed herein may bepracticed in the absence of any compound or element (or group ofcompounds or elements) which is not specifically disclosed herein.

Polyquaternium Compound

The compositions of the present invention comprise a polyquaterniumcompound. Polyquaternium is the International Nomenclature for CosmeticIngredients designation for several polycationic polymers that are usedin the personal care industry. These polymers have quaternary ammoniumcenters in the polymer. INCI has approved at least 37 different polymersunder the polyquaternium designation. They are cationic molecules. Somehave antimicrobial properties, and find particular application inconditioners, shampoo, hair mousse, hair spray, hair dye, and contactlens solutions. Different polymers are distinguished by the numericalvalue that follows the word “polyquaternium”. The numbers are assignedin the order in which they are registered rather than because of theirchemical structure. Some of the more common quaternary ammoniumcompounds include those generically referred to in the art aspolyquaternium.

In some embodiments, the composition will contain a polyquaterniumhaving a weight average molecular weight of from about 150 to about15,000 Daltons, optionally from about 200 to about 13,500 Daltons, oroptionally from about 250 to about 12,000 Daltons in a level of fromabout 10 ppm to about 1000 ppm, or from about 12 ppm to about 200 ppm,or from about 15 ppm to about 65 ppm of a polyquaternium.

Examples of suitable polyquaternium compounds include, but are notlimited to, polyquatemium-1, polyquaternium-10, polyquaternium-42 ormixtures. In an embodiment of the present invention, the polyquaterniumcompound is polyquaternium-42.

Polyquatemium-1 is also known as ethanol, 2,2′,2″-nitrilotris-, polymerwith 1,4-dichloro-2-butene andN,N,N′,N′-tetramethyl-2-butene-1,4-diamine. Polyquatemium-10 is alsoknown as quaternized hydroxyethyl cellulose. Polyquatemium-42 is alsoknown as poly[oxyethylene(dimethylimino)ethylene (dimethylimino)ethylenedichloride].

Polyquaternium compounds are generally known to form precipitates withanionic polymers. In some instances, concentrations of the results inthe precipitate formation and/or complexation with anionic polymerspresent in the composition.

Anionic Polymer

The compositions of the present invention comprise an anionic polymerhaving a weight average molecular weight of from about 250 to about4,000, 000, optionally from about 50,000 to about 3,000,000, optionallyfrom about 75,000 to about 2,000,000, or optionally from about 100,000to about 1,500,000 Daltons. Anionic polymers are polymers formed byanionic addition polymerization. Anionic addition polymerization is aform of chain-growth polymerization or addition polymerization thatinvolves the polymerization of vinyl monomers with strongelectronegative group. As noted above, these polymers would normally bedismissed as incompatible with cationic compounds (i.e. would form aprecipitate in the combination with cationic compounds).

Examples of suitable anionic polymers, include, but are not limited to:sodium alginate (alginate), linear sulphated polysaccharides that areextracted from red edible seaweeds (carageenans), carbo-benzens(carbomers), high molecular weight, non-linear polyacrylic acidcross-linked with polyalkenyl polyethers sold under the trade nameCARBOPOL (Lubrizol Advanced Materials, Inc. Cleveland, Ohio), sodiumcarboxymethylcellulose (sodium CMC), internally cross-linked sodiumcarboxymethylcelluloses (Croscarmellose sodium), water-solublepolysaccharides produced by Pseudomonas elodea, a bacterium also knownas gellan gum (in certain embodiments the low acyl form of gellan gum isused) such as those sold under the trade name KELCOGEL (CP Kelco U.S.,Inc., Atlanta, Ga.), anionic, nonsulfated glycosaminoglycans known asHyaluronan (also called hyaluronic acid or hyaluronate or HA),structural heteropolysaccharides known as Pectin, polysaccharidessecreted by the bacterium Xanthomonas campestris known as Xanthan Gumsuch as those sold under the trade name KELTROL (CP Kelco U.S., Inc.,Atlanta, Ga.), maleic/alkylvinyl ether copolymers such as those soldunder the trade name Gantrez (Ashland, N.J.) and mixtures of thereof.

In some embodiments, the composition will contain an anionic polymer ina level from about 0.001 to about 0.5%, or from about 0.005% to about0.25%, or from about 0.01% to about 0.2% anionic polymer.

Hyaluronic acid is a linear polysaccharide (long-chain biologicalpolymer) formed by repeating disaccharide units consisting ofD-glucuronic acid and N-acetyl-D-glucosamine linked by β(1-3) and β(1-4)glycosidic linkages. Hyaluronic acid is distinguished from the otherglycosaminoglycans, as it is free from covalent links to protein andsulphonic groups. Hyaluronic acid is ubiquitous in animals, with thehighest concentration found in soft connective tissue. It plays animportant role for both mechanical and transport purposes in the body;e.g., it gives elasticity to the joints and rigidity to the vertebratediscs, and it is also an important component of the vitreous body of theeye.

Hyaluronic acid is accepted by the ophthalmic community as a compoundthat can protect biological tissues or cells from compressive forces.Accordingly, hyaluronic acid has been proposed as one component of aviscoelastic ophthalmic composition for cataract surgery. Theviscoelastic properties of hyaluronic acid, that is, hard elastic understatic conditions though less viscous under small shear forces enableshyaluronic acid to basically function as a shock absorber for cells andtissues. Hyaluronic acid also has a relatively large capacity to absorband hold water. The stated properties of hyaluronic acid are dependenton the molecular weight, the solution concentration, and physiologicalpH. At low concentrations, the individual chains entangle and form acontinuous network in solution, which gives the system interestingproperties, such as pronounced viscoelasticity and pseudoplasticity thatis unique for a water-soluble polymer at low concentration.

In certain embodiments, the maleic/alkylvinyl ether copolymer includedin embodiments of the present invention may have a weight averagemolecular weight of between about 200,000 Daltons and about 1,500,000Daltons, and/or a polydispersity index of between about 2 and 6. Themaleic and alkylvinyl ether monomer segments may be randomly arranged inone embodiment. In another embodiment the monomer segments arealternating such that the resulting maleic/alkylvinyl ether copolymerhas a structure similar to that illustrated by the following generalmaleic methylvinyl ether copolymer structure:

In certain embodiments, the compositions of the present inventioncomprise the free acid of methyl vinyl ether/maleic anhydride copolymerhaving a weight average molecular weight of between about 200,000Daltons and about 1,500, 000 Daltons, optionally from 200,000 Daltons toabout 700,000 Daltons. In one embodiment, the free acid methyl vinylether/maleic anhydride copolymer is Gantrez® S-95 which has an averageweight-average molecular weight of about 216,000 Daltons. In anotherembodiments, the free acid methyl vinyl ether/maleic anhydride copolymeris Gantrez® S-96 which has a weight-average molecular weight of about700,000 Daltons.

Mixtures of maleic/alkylvinyl ether copolymers may also be employed. Inone embodiment, a composition of the of the present invention maycontain at least about 1% by weight (active amount) maleic/alkylvinylether copolymer, more particularly between about 1% and 15% by weightmaleic/alkylvinyl ether copolymer, even more particularly, between about1% and 10% by weight maleic/alkylvinyl ether copolymer.

In some embodiments, the anionic polymer is selected from the groupconsisting of hyaluronic acid (HA), gellan gum, methyl vinylether/maleic anhydride copolymer (optionally, the free acid thereof) ormixtures thereof.

Organic Acid

The compositions of the present invention comprise an organic acid,salts thereof (such the sodium or potassium salts of the organic acids)and mixtures of any of the preceding components. In certain embodiments,the organic acid has a solubility of at least 10 (or about 10) g/100 mlwater at 25° C., optionally, at least 20 (or about 20) g/100 ml water at25° C., optionally, at least 30 (or about 30) g/100 ml water at 25° C.,optionally, at least 40 (or about 40) g/100 ml water at 25° C.,optionally, at least 50 (or about 50) g/100 ml water at 25° C., or,optionally, at least 60 (or about 60) g/100 ml water at 25° C. and,optionally, no greater than 150 (or about 150) g/100 ml water at 25° C.. Table 1 shows select list of organic acids and their solubility ascited in Merck Index, Twelfth Edition, Whitehouse Station, N.J. 1996.

TABLE 1 Solubility of Select Organic Acids Solubility (g/100 ml OrganicAcid water at 25° C.) Formic acid >100 Acetic acid 100 Propionicacid >100 Oxalic acid 8.34 Succinic acid 8 Glutaric acid 63.9 Maleicacid 78 Fumaric acid 0.63 Adipic acid about 1 L-Tartaric acid >100Citric acid 59.2 Sodium Citrate, Dihydrate about 77Ethylenediaminetetraacetic acid 0.05

Suitable organic acids of the present invention include, but are notlimited to, carboxylic acids, dicarboxylic acids, tricarboxylic acids,salts thereof, and mixtures thereof.

Examples of carboxylic acids include, but are not limited to, formicacid, acetic acid, propionic acid, salts thereof, and mixtures thereof.

Examples of dicarboxylic acids include, but are not limited to, glutaric(i.e. pentanedioic) acid, maleic acid, tartaric acid, salts thereof, andmixtures thereof.

Examples of tricarboxylic acids include, but are not limited to, citricacid, isocitric acid, salts thereof and mixtures thereof.

The tricarboxylic acid citric acid is a weak organic acid with theformula C₆H₈O_(7.) It is a natural preservative/conservative whichoccurs naturally in citrus fruits and is also used to add an acidic orsour taste to foods and drinks. In biochemistry, the conjugate base ofcitric acid, citrate, is important as an intermediate in the citric acidcycle, which occurs in the metabolism of all aerobic organisms. Itconsists of 3 carboxyl (R—COOH) groups.

In certain embodiments, the organic acid is selected from the groupconsisting of carboxylic acids, dicarboxylic acids, tricarboxylic acids,salts thereof and mixtures thereof. In one embodiment, the organic acidis citric acid. In another embodiment, the organic acid is tartaricacid.

In some embodiments, the composition will contain a molar ratio oforganic acid to monomer unit of the polyquaternium compound of at least1:1 (or about 1:1), optionally, at least 10:1 (or about 10:1),optionally, at least 100:1 (or about 100:1), optionally, at least 250:1(or about 250:1), optionally, at least 350:1 (or about 350:1), or,optionally, at least 1000:1 (or about 1000:1). Optionally, the molarratio of the organic acid to monomer unit of the polyquaternium compoundis no greater than 5000:1 (or about 5000:1), or, optionally, no greaterthan 10,000:1 (or about 10,000:1).

In certain embodiments, a premix of the polyquaternium compound and theorganic acid of the present invention or a premix of the anionic polymerand the organic acid of the present invention is formed prior to mixingof the polyquaternium compound and the anionic polymer.

The compositions of present invention are substantially free of cationicoligomer compounds and precipitation inhibiting compounds. The term“precipitation inhibiting compounds” means compounds, other than theorganic acids of the present invention, which inhibit, reduce, orprevent the precipitation of the polyquaternium compounds and theanionic polymers. Examples of precipitation inhibiting compoundsinclude, but are not limited to, amphoteric surfactants having a weightaverage molecular weight of greater than 303 (or about 303) Daltons.Amphoteric surfactants have the general formula I:

wherein R¹ is R or —(CH₂)n—NHC(O)R, wherein R is a C₈-C₃₀ alkyloptionally substituted with hydroxyl and n is 2,3, or 4; R² and R³ areeach independently selected from the group consisting of hydrogen andC₁-C₄ alkyl; R⁴ is a C₂-C₈ alkylene optionally substituted withhydroxyl; and SO₃— can also be further substituted by CO₂ —. Theinvention would also exclude alkylamido betaines such asalkylamidopropyl betaines, cocoamidopropyl betaine, and lauroylamidopropyl dimethyl betaine. Such amphoteric surfactants are useful inremoving proteins and lipids and may, therefore, disrupt tear lipids inthe eye which are essential to preventing evaporation of tear film.Accordingly, they are not desired for the compositions of this inventionwhich are intended for instillation in the eye.

As noted above, the compositions of the present invention are alsosubstantially free of cationic oligomers or nitrogen/amine oligomershaving a number average molecular weight (MNO) from 500 Daltons to15,000 Daltons (hereinafter referred to as cationic oligomer compounds),wherein the cationic oligomer or nitrogen/amine oligomer is present inthe composition from 0.01 wt. % to 1.0 wt. %, and the compositioncomprises a ratio MNO: MNA from 5:1 to 1:5. Cationic oligomer compoundsin contact lens solutions are intended to compete with cationicantimicrobial components to minimize adsorption of the cationic compoundonto contact lenses. Without being limited by theory, it is believed,however, that such competition may compromise the activity of thepolyquaternium compound in the compositions of the present invention.

The term “substantially free” as related to the cationic oligomercompounds and precipitation inhibiting compounds means that the oligomercompounds and/or the precipitation inhibiting compounds are present inthe compositions of the present invention at a concentration of lessthan 5% (or about 5%), optionally less than 2.5% (or about 2.5%), andoptionally less than 1% (or about 1%), optionally less than 0.1% (orabout 0.1%), or optionally less than 0.01% (or about 0.01%). Optionally,the compositions of the present invention are free of cationic oligomercompounds and precipitation inhibiting compounds.

Optional Components

The compositions of the present invention may optionally comprise one ormore additional excipients and/or one or more additional activeingredients. Excipients commonly used in ophthalmic compositionsinclude, but are not limited to, demulcents, tonicity agents,preservatives, chelating agents, buffering agents (other than and inaddition to the organic acids of the present invention), andsurfactants. Other excipients comprise solubilizing agents, stabilizingagents, comfort-enhancing agents, polymers, emollients, pH-adjustingagents (other than and in addition to the organic acids of the presentinvention), and/or lubricants. Any of a variety of excipients may beused in the compositions of the present invention including water,mixtures of water and water-miscible solvents, such as vegetable oils ormineral oils comprising from 0.5% to 5% non-toxic water-solublepolymers, natural products, such as agar and acacia, starch derivatives,such as starch acetate and hydroxypropyl starch, and also othersynthetic products such as polyvinyl alcohol, polyvinylpyrrolidone,polyvinyl methyl ether, polyethylene oxide, and preferably cross-linkedpolyacrylic acid and mixtures thereof.

Demulcents or soothing agents used with embodiments of the presentinvention include, but are not limited to, cellulose derivatives (suchhydroxyethyl cellulose, methyl cellulose, hypromellose or mixturesthereof), glycerin, polyvinyl pyrrolidone, polyethylene oxide,polyethylene glycol, propylene glycol and polyacrylic acid. In certainembodiments, propylene glycol and polyethylene glycol 400 are thedemulcents.

Suitable tonicity-adjusting agents include, but are not limited to,mannitol, sodium chloride, glycerin, and the like. Suitable bufferingagents include, but are not limited to, phosphates, borates, acetatesand the like, and amino alcohols such as 2-amino-2-methyl-1-propanol(AMP), salts of any of the above and mixtures of any of the abovementioned agents. Suitable surfactants include, but are not limited to,ionic and nonionic surfactants (though nonionic surfactants arepreferred), RLM 100, POE 20 cetylstearyl ethers such as Procol® CS20,poloxamers such as Pluronic® F68, and block copolymers such aspoly(oxyethylene)-poly(oxybutylene) compounds set forth in U.S. PatentApplication Publication No. 2008/0138310 entitled “Use of PEO-PBO BlockCopolymers in Ophthalmic Compositions” filed Dec. 10, 2007 (whichpublication is herein incorporated by reference).

Compositions of the present invention are ophthalmically suitable forapplication to a subject's eyes. The term “aqueous” typically denotes anaqueous formulation wherein the excipient is >about 50%, morepreferably >about 75% and in particular >about 90% by weight water.These drops may be delivered from a single dose ampoule which maypreferably be sterile and thus render bacteriostatic components of theformulation unnecessary. Alternatively, the drops may be delivered froma multi-dose bottle which may preferably comprise a device whichextracts any preservative from the composition as it is delivered, suchdevices being known in the art.

In certain embodiments, the compositions of the present invention areisotonic, or slightly hypotonic in order to combat any hypertonicity oftears caused by evaporation and/or disease. This may require a tonicityagent to bring the osmolality of the formulation to a level at or near210-320 milliosmoles per kilogram (mOsm/kg). The compositions of thepresent invention generally have an osmolality in the range of 220-320mOsm/kg, or, optionally, have an osmolality in the range of 235-300mOsm/kg. The ophthalmic compositions will generally be formulated assterile aqueous solutions.

The compositions of the present invention can also be used to administerpharmaceutically active compounds. Such compounds include, but are notlimited to, glaucoma therapeutics, pain relievers, anti-inflammatory andanti-allergy medications, and anti-microbials. More specific examples ofpharmaceutically active compounds include betaxolol, timolol,pilocarpine, carbonic anhydrase inhibitors and prostglandins;dopaminergic antagonists; post-surgical antihypertensive agents, such aspara-amino clonidine (apraclonidine); anti-infectives such asciprofloxacin, moxifloxacin, and tobramycin; non-steroidal and steroidalanti-inflammatories, such as naproxen, diclofenac, nepafenac, suprofen,ketorolac, tetrahydrocortisol and dexamethasone; dry eye therapeuticssuch as PDE4 inhibitors; and anti-allergy medications such as H1/H4inhibitors, H4 inhibitors, olopatadine or mixtures thereof.

It is also contemplated that the concentrations of the ingredientscomprising the formulations of the present invention can vary. A personof ordinary skill in the art would understand that the concentrationscan vary depending on the addition, substitution, and/or subtraction ofingredients in a given formulation.

In certain embodiments, the compositions of the present invention arebuffered, using buffering agents, such that the compositions maintain apH of from about 5.0 to a pH of about 8.0, optionally a pH of from about6.5 to a pH of about 8.0. Topical formulations (particularly topicalophthalmic formulations, as noted above) are preferred which have aphysiological pH matching the tissue to which the formulation will beapplied or dispensed.

In certain embodiments, the compositions of the present invention is inthe form of eye-drop solution, eye wash solution, contact lenslubricating and/or rewetting solution, spray, mist or any other mannerof administering a composition to the eye.

In particular embodiments, the composition of the present invention areformulated for administration at any frequency of administration,including once a week, once every five days, once every three days, onceevery two days, twice a day, three times a day, four times a day, fivetimes a day, six times a day, eight times a day, every hour, or greaterfrequency. Such dosing frequency is also maintained for a varyingduration of time depending on the therapeutic needs of the user. Theduration of a particular therapeutic regimen may vary from one-timedosing to a regimen that extends for months or years. One of ordinaryskill in the art would be familiar with determining a therapeuticregimen for a specific indication.

EXAMPLES

The compositions of the present invention as described in followingexamples illustrate specific embodiments of compositions of the presentinvention, but are not intended to be limiting thereof. Othermodifications can be undertaken by the skilled artisan without departingfrom the spirit and scope of this invention.

Example 1: Solution with Anionic Polymer and Polyquaternium Compound

A solution was prepared containing both an anionic polymer (Gellan Gum)and a Polyquaternium compound (PQ42). Table 2 shows the list ofingredients.

TABLE 2 Example 1 components. amount per INGREDIENT % w/w batch (gms)Hypromellose 0.200 0.150 Gellan Gum 0.020 0.015 Polyquaternium 42 0.0030.00225 Sodium Citrate, 1.755 1.316 Dihydrate Purified Water 98.02273.5165 total 100.00% 75.00 g

The hypromellose was Methocel E4M Premium, supplied by DOW CHEMICAL(MIDLAND, Mich.). The gellan gum was Kelcogel CG-LA low acyl, suppliedby CP KELCO (ATLANTA, Ga.). The Polyquaternium 42 was supplied asPolyquaternium 42 (33% aqueous) by DSM BIOMEDICAL (BERKELEY, Calif.).The sodium citrate, dihydrate was tri-Sodium Citrate Dihydrate Powdersupplied by MERCK (DARMSTADT, GERMANY).

The procedure for preparing the solution was as follows:

-   1. The 1.316 grams of Sodium Citrate Dihydrate was added to 45 grams    of Purified Water USP in a container. The solution was mixed until    the Sodium Citrate Dihydrate dissolved.-   2. To the above was added 0.225 grams of a 1% solution of    Polyquaternium 42 in water. The solution was mixed until the    Polyquaternium 42 dissolved.-   3. An additional 3.46 grams of water was added and mixed until the    solution was uniform.-   4. In a separate a container, a 1 liter solution of 0.06% Gellan Gum    and 0.60% Hypromellose was prepared by adding 0.60 grams of Gellan    Gum slowly to 950 g of water heated to a temperature greater than    40° C. The temperature of the solution was increased to 75° C. while    mixing. When a temperature of 75° C. was achieved, the solution was    mixed for 15 minutes, while maintaining a constant temperature of    75° C. The temperature of the solution was then increased to 80° C.    to 85° C. To this solution, 6 grams of Hypromellose was then slowly    added. When addition of Hypromellose was completed, the temperature    was kept constant from 80° C. to 85° C. for 15 minutes. The solution    was mixed until ambient temperature, q.s.ed with water, and mixed an    additional 15 minutes.-   5. To the solution of Step 3 was slowly added 25 grams of the 0.06%    Gellan Gum and 0.60% Hypromellose solution of Step 4.

On completion of addition of all ingredients, it was noted that thesolution containing the sodium citrate as the organic acid was clearregardless of the solution containing both Gellan Gum and Polyquaternium42. The sodium citrate, dihydrate used in this example had a solubilityfrom Table 1 of about 77 g/100 ml of water (at 25° C.)—or a solubilitygreater than the 10 g/100 ml threshold solubility (at 25° C.) fororganic acids useful in the present invention.

Example 2: Solutions with Anionic Polymer and Polyquaternium Compound

A solution was prepared containing both an anionic polymer (Gellan Gum)and a Polyquaternium compound (PQ42). Table 3 shows the list ofingredients.

TABLE 3 Example 2 components. 2A 2B amount per amount per INGREDIENT %w/w batch (gms) % w/w batch (gms) Hypromellose 0.200 0.150 0.200 0.150Gellan Gum 0.020 0.015 0.020 0.015 Polyquaternium 42 0.003 0.00225 0.0030.00225 Sodium Citrate, 0.1368 0.1026 1.368 1.026 Dihydrate PurifiedWater 99.6402 74.73015 98.409 73.80675 total 100.00% 75.00 g 100.00%75.00 g

The hypromellose was Methocel E4M Premium, supplied by DOW CHEMICAL(MIDLAND, Mich.). The gellan gum was Kelcogel CG-LA low acyl, suppliedby CP KELCO (ATLANTA, Ga.). The Polyquaternium 42 was supplied asPolyquaternium 42 (33% aqueous) by DSM BIOMEDICAL (BERKELEY, Calif.).The sodium citrate, dihydrate was tri-Sodium Citrate Dihydrate Powder,supplied by MERCK (DARMSTADT, GERMANY).

The procedure for preparing the solutions was as follows:

-   1. The Sodium Citrate Dihydrate was added to 45 grams of Purified    Water USP. The solution was mixed until the Sodium Citrate Dihydrate    dissolved.-   2. To the above was added 0.225 grams of a 1% solution of    Polyquaternium 42 in water. The solution was mixed until the    Polyquaternium 42 dissolved.-   3. The additional of water was added and mixed until the solution    was uniform.-   4. Slowly added to the solution of Step 3 was 25 grams of a 0.06%    Gellan Gum and 0.60% Hypromellose solution as prepared in Step 4 of    Example 1.

On completion of addition of all ingredients, it was noted that Solution2A having a molar ratio of sodium citrate to monomer unit ofPolyquaternium 42 of about 40:1 was slightly cloudy yet uniform,indicating that insufficient Citrate was available to preventincompatibility of Gellan Gum and Polyquaternium 42. Solution 2B havinga molar ratio of sodium citrate to monomer unit of Polyquaternium 42 ofabout 400:1 was clear regardless of the solution containing both GellanGum and Polyquaternium 42. The sodium citrate, dihydrate used in thisexample had a solubility from Table 1 of about 77 g/100 ml of water (at25° C.)—or a solubility greater than the 10 g/100 ml thresholdsolubility (at 25° C.) for organic acids useful in the presentinvention. This example shows that there is a finite ratio of citrate tocationic polyquaternium needed to overcome incompatibility with anionicpolymer.

Example 3: Solutions with Anionic Polymer and Polyquaternium Compound

A solution was prepared containing both and anionic polymer (SodiumHyaluronate) and a Polyquaternium compound (PQ42). Table 4 shows thelist of ingredients.

TABLE 4 Example 3 components. 3A 3B 3C amount amount amount per per perIN- batch batch batch GREDIENT % w/w (gms) % w/w (gms) % w/w (gms)Sodium 0.200 0.100 0.200 0.100 0.200 0.100 Hyaluronate Poly- 0.0030.0015 0.003 0.0015 0.003 0.0015 quaternium 42 Sodium — — 2.000 1.0002.000 1.000 Citrate, Dihydrate Citric Acid, — — 0.100 0.050 0.100 0.050anhydrous Purified 99.797 49.8985 97.697 48.8485 97.697 48.8485 Watertotal 100.00% 50.00 g 100.00% 50.00 g 100.00% 50.00 g

The sodium hyaluronate was supplied by LIFECORE (CHASKA, MN). ThePolyquaternium 42 was supplied as Polyquaternium 42 (33% aqueous) by DSMBIOMEDICAL (BERKELEY, Calif.). The sodium citrate, dihydrate wastri-Sodium Citrate Dihydrate Powder supplied by MERCK (DARMSTADT,GERMANY). The citric acid anhydrous was supplied by VWR/BDH (WESTCHESTER, Pa.).

The procedure for preparing the Solution 3A was as follows:

-   1. Into a beaker was poured 16.67 grams of a 0.6% Sodium Hyaluronate    Solution which was prepared by adding 150 grams of water into a    separate container and slowly adding 1 gram of Sodium Hyaluronate    into the water. The solution was mixed for 2 hours at ambient    temperature to disperse the Sodium Hyaluronate. Additional water was    added to bring the total amount of the solution to 166 grams and    mixing the solution an additional 10 minutes.-   2. Next, 32.33 grams of Purified Water USP was added to the beaker    while mixing to disperse and solubilize.-   3. One gram of a solution of 0.015 grams of Polyquaternium 42 in 10    grams of Purified Water US was added to the above while mixing.

The procedure for preparing the Solution 3B was as follows:

-   1. Into a beaker was poured 16.67 grams of a 0.6% Sodium Hyaluronate    Solution as prepared in Step 1 of the preparation of Solution 3A.-   2. Next, 22.28 grams of Purified Water USP was added to the first    beaker while mixing to disperse and solubilize.-   3. Into a second beaker, 8.9485 grams of Purified Water USP was    poured.-   4. Next, 0.015 grams of Polyquaternium 42 was added to the second    beaker while mixing.-   5. One gram of Sodium Citrate Dihydrate and 0.050 grams of Citric    Acid were added to the second beaker while mixing to disperse with    Polyquaternium 42 premix.-   6. The solution in the second beaker was added to the solution in    the first beaker while mixing.

The procedure for preparing the Solution 3C was as follows:

-   1. Into a beaker was poured 16.67 grams of a 0.6% Sodium Hyaluronate    Solution as prepared in Step 1 of the preparation of Solution 3A.-   2. Next, 23.28 grams of Purified Water USP was added to the beaker    while mixing to disperse and solubilize.-   3. One gram of Sodium Citrate Dihydrate was added to the beaker    while mixing.

4. Next, 0.050 grams of Citric Acid were added to the beaker whilemixing.

-   5. Finally, 0.0045 grams of a solution of 33% Polyquaternium 42 was    added to the beaker while mixing.

Solution 3A was extremely cloudy with evidence of a local precipitateindicative of incompatibility of Sodium Hyaluronate with Polyquaternium42. Solutions 3B and 3C containing the sodium citrate, dihydrate/citricacid combination as the organic acid were clear regardless of the factthat the anionic polymer Sodium Hyaluronate was combined withPolyquaternium 42. The sodium citrate, dihydrate and citric acid used inthis example had a solubilities from Table 1 of about 77 g and 59.2 g/100 ml of water (at 25° C.), respectively—or solubilities greater thanthe 10 g/100 ml threshold solubility (at 25° C.) for organic acidsuseful in the present invention.

It is important to note that in Solutions 3B and 3C that the citrate wasadded and dissolved first with Polyquaternium 42 prior to combining withthe anionic polymer or added and dissolved first with anionic polymerbefore combining with Polyquaternium 42.

Example 4: Solutions with Anionic Polymer and Polyquaternium Compound

A solution was prepared containing both and anionic polymer (Gellan Gum)and a Polyquaternium compound (PQ42). Table 5 shows the list ofingredients.

TABLE 5 Example 4 components. 4A 4B 4C amount amount amount per per perIN- batch batch batch GREDIENT % w/w (gms) % w/w (gms) % w/w (gms)Hypro- 0.200 0.100 0.200 1.000 0.200 1.000 mellose Gellan Gum 0.0200.010 0.020 0.100 0.020 0.100 Polyethylene — — — — 1.129 5.645 Glycol400 Glycerin — — — — 0.2527 1.264 Sodium 2.000 1.000 2.000 10.000 2.00010.000 Citrate, Dihydrate Citric Acid 0.10 0.05 0.100 0.500 0.010 0.050Poly- 0.003 0.0015 0.003 0.0015 0.003 0.015 quaternium 42 Edetate — —0.100 0.5 0.10 0.500 Disodium Purified 97.677 48.8385 97.577 487.88596.2853 481.426 Water total 100.00% 50.00 g 100.00% 500.00 g 100.00%500.00 g

The hypromellose was Methocel E4M Premium, supplied by DOW CHEMICAL(MIDLAND, Mich.). The gellan gum was Kelcogel CG-LA low acyl, suppliedby CP KELCO (ATLANTA, Ga.). The Polyethylene Glycol 400 was Polyglykol400 supplied by CLAMANT PRODUKTE (BURGKIRCHEN, GERMANY). The Glycerinwas Edenor G 99.8 supplied by EMERY OLEOCHEMICALS (DUSSELDORF, GERMANY).The Polyquaternium 42 was supplied as Polyquaternium 42 (33% aqueous) byDSM BIOMEDICAL (BERKELEY, Calif.). The sodium citrate, dihydrate wastri-Sodium Citrate Dihydrate Powder supplied by MERCK (DARMSTADT,GERMANY). The citric acid anhydrous was supplied by VWR/BDH (WESTCHESTER, Pa.). The edetate disodium was Titriplex III supplied by MERCK(MOLLET DEL VALLES, SPAIN).

The procedure for preparing the Solution 4A was as follows:

-   1. 16.67 grams of a 0.6% Gellan Gum and 0.06% Hypromellose solution    as prepared in

Step 4 of Example 1 was added to a beaker.

-   2. 32.2655 grams of Purified Water USP was added to the beaker while    mixing to disperse and dissolve the gellan gum and hypromellose.-   3. Sequentially added the Sodium Citrate Dihydrate and Citric acid    allowing time for the prior to dissolve before adding the latter.-   4. 0.0045 grams of a solution of 33% Polyquaternium 42 was added to    the beaker while mixing.

The procedure for preparing the Solution 4B was as follows:

-   1. Into a beaker was poured 166.7 grams of a 0.6% Gellan Gum and    0.06% Hypromellose solution as prepared in Step 4 of Example 1.-   2. Next, 322.255 grams of Purified Water USP was added to the beaker    while mixing to disperse and dissolve the gellan gum and    hypromellose.-   3. Sequentially added the 10 grams of Sodium Citrate Dihydrate and    0.5 grams of Citric acid allowing time for the prior to dissolve    before adding the latter.-   4. While mixing, 0.045 grams of a solution of 33% Polyquaternium 42    was added to the beaker.

5. Added 0.5 grams of Edetate Disodium and mixed the batch untildissolved.

The procedure for preparing the Solution 4C was as follows:

-   1. Into a beaker was poured 166.7 grams of a 0.6% Gellan Gum and    0.06% Hypromellose solution as prepared in Step 4 of Example 1.-   2. Next, 315.346 grams of Purified Water USP was added to the beaker    while mixing to disperse and dissolve the gellan gum and    hypromellose.-   3. Sequentially added 5.645 g of Polyethylene Glycol 400 and 1.264 g    of Glycerin, allowing time for each to dissolve before proceeding.-   4. Sequentially added the 10 grams of Sodium Citrate Dihydrate and    0.5 grams of Citric acid allowing time for the prior to dissolve    before adding the latter.-   5. While mixing, 0.045 grams of a solution of 33% Polyquaternium 42    was added to the beaker.-   6. Added 0.5 grams of Edetate Disodium and mixed the batch until    dissolved.

All three solutions containing the sodium citrate, dihydrate/citric acidcombination as the organic acid were clear. The sodium citrate,dihydrate and citric acid used in this example had solubilities fromTable 1 of about 77 g and 59.2 g /100 ml of water (at 25° C.),respectively—or solubilities greater than the 10 g/100 ml thresholdsolubility (at 25° C.) for organic acids useful in the presentinvention. The tonicity of Solutions 4A and 4C were measured using acalibrated Advanced Instruments Osmometer (model 3320) supplied byAdvanced

Instruments (Norwood, Mass.). The tonicity of Solution 4A was 215mOsm/Kg. This is suitable for a hypotonic ophthalmic solution. Thetonicity of Solution 4C was 292 mOsm/Kg. This is suitable for a isotonicophthalmic solution.

Example 5: Solutions with Anionic Polymer and Polyquaternium

A solution was prepared containing both and anionic polymer (Gellan Gum)and a Polyquaternium (PQ42). Table 6 shows the list of ingredients.

TABLE 6 Example 5 components. 5A 5B amount per amount per INGREDIENT %w/w batch (gms) % w/w batch (gms) Hypromellose 0.200 1.000 0.200 1.000Gellan Gum 0.020 0.100 0.020 0.100 Polyethylene 1.129 5.645 1.129 5.645Glycol 400 Glycerin 0.2527 1.264 0.2527 1.264 Sodium Citrate, 1.4007.000 1.600 8.000 Dihydrate Boric Acid 0.500 2.500 0.580 2.900Polyquaternium 42 0.003 0.015 0.003 0.015 Edetate Disodium 0.10 0.5000.10 0.500 Purified Water 96.3953 481.976 96.1153 480.576 total 100.00%500.00 g 100.00% 500.00 g

The hypromellose was Methocel E4M Premium, supplied by DOW CHEMICAL(MIDLAND, Mich.). The gellan gum was Kelcogel CG-LA low acyl, suppliedby CP KELCO (ATLANTA, Ga.). The Polyethylene Glycol 400 was Polyglykol400 supplied by CLAMANT PRODUKTE (BURGKIRCHEN, GERMANY). The Glycerinwas Edenor G 99.8 supplied by EMERY OLEOCHEMICALS (DUSSELDORF, GERMANY).The Boric acid was supplied by MERCK (DARMSTADT, GERMANY). ThePolyquaternium 42 was supplied as Polyquaternium 42 (33% aqueous) by DSMBIOMEDICAL (BERKELEY, Calif.). The sodium citrate, dihydrate wastri-Sodium Citrate Dihydrate Powder, supplied by MERCK (DARMSTADT,GERMANY). The citric acid anhydrous was supplied by VWR/BDH (WESTCHESTER, Pa.). The edetate disodium was Titriplex III supplied by MERCK(MOLLET DEL VALLES, SPAIN).

The procedure for preparing the Solution 5A was as follows:

-   1. Into a beaker was poured 166.7 grams of a 0.6% Gellan Gum and    0.06% Hypromellose solution as prepared in Step 4 of Example 1.-   2. Next, 308.3 grams of Purified Water USP was added to the beaker    while mixing to disperse and dissolve the gellan gum and    hypromellose.-   3. Sequentially added 5.645 g of Polyethylene Glycol 400 and 1.264 g    of Glycerin, allowing time for each to dissolve before proceeding.-   4. Next, added the 4 grams of Sodium Citrate Dihydrate and mix until    dissolved.-   5. While mixing, 0.045 grams of a solution of 33% Polyquaternium 42    was added to the beaker.-   6. Added 0.5 grams of Disodium Edetate and mixed the batch until    dissolved.-   7. The following ingredients are added in sequence and dissolved to    adjust pH of the final solution:

1.6 gm Boric acid, 2 gm Sodium Citrate Dihydrate, 0.5 gm Boric acid, 1gm Sodium Citrate Dihydrate, and 0.4 gm Boric acid.

The procedure for preparing the Solution 5B was as follows:

-   1. Into a beaker was poured 166.7 grams of a 0.6% Gellan Gum and    0.06% Hypromellose solution as prepared in Step 4 of Example 1.-   2. Next, 308.3 grams of Purified Water USP was added to the beaker    while mixing to disperse and dissolve the gellan gum and    hypromellose.-   3. Sequentially added 5.645 g of Polyethylene Glycol 400 and 1.264 g    of Glycerin, allowing time for each to dissolve before proceeding.-   4. Next, added the 8 grams of Sodium Citrate Dihydrate and mix until    dissolved.-   5. While mixing, 0.045 grams of a solution of 33% Polyquaternium 42    was added to the beaker.-   6. Added 0.5 grams of Disodium Edetate and mixed the batch until    dissolved.-   7. Added 2.9 grams of Boric acid and mixed the batch until    dissolved.-   8. Sufficient water was added to bring the batch total to 500 grams.

Both solutions containing the sodium citrate, dihydrate as the organicacid were clear. The sodium citrate, dihydrate used as the organic acidin this example had a solubility from Table 1 of about 77 g/100 ml ofwater (at 25° C.)—or a solubility greater than the 10 g/100 ml thresholdsolubility (at 25° C.) for organic acids useful in the presentinvention. The tonicity of Solution 5A was measured as discussed inExample 4 above. The tonicity of Solution 5A was 290 mOsm/Kg. This issuitable for an isotonic ophthalmic solution. The pH of Solution 5A was6.8, within the pH of natural tears. The pH of Solution 5B was 7.0.

Example 6: Solutions with Anionic Polymer and Polyquaternium

A solution was prepared containing both and anionic polymer (SodiumHyaluronate) and a Polyquaternium (PQ42). Table 7 shows the list ofingredients.

TABLE 7 Example 6 components. 6A 6B amount per amount per INGREDIENT %w/w batch (gms) % w/w batch (gms) Sodium 0.200 0.200 0.200 0.200Hyaluronate Polyquaternium 42 0.005 0.005 0.005 0.005 Sodium Citrate,0.350 0.350 0.350 0.350 Dihydrate Citric Acid, 0.009 0.009 — — anhydrousPurified Water 99.436 99.436 99.445  99.445  1N Sodium * * — — Hydroxide1N Hydrochloric * * — — Acid total 100.00% 100.000 0.10  0.500 *Toadjust pH

The Sodium Hyaluronate was supplied by LIFECORE (CHASKA, Minn.). ThePolyquaternium 42 was supplied as Polyquaternium 42 (33% aqueous) by DSMBIOMEDICAL (BERKELEY, Calif.). The sodium citrate, dihydrate wastri-Sodium Citrate Dihydrate Powder supplied by MERCK (DARMSTADT,GERMANY). The citric acid anhydrous was supplied by VWR/BDH (WESTCHESTER, Pa.).

The procedure for preparing the Solution 6A was as follows:

-   1. Into a beaker was poured 99 grams of a solution of 0.2% Sodium    Hyaluronate which was prepared by adding 988 grams of water into a    separate container and slowly adding 2 gram of Sodium Hyaluronate    into the water. The solution was mixed for 2 hours at ambient    temperature to disperse the Sodium Hyaluronate. Additional water was    added to bring the total amount of the solution to 990 grams and    mixing the solution an additional 10 minutes.-   2. Next, 0.009 grams of Citric Acid was added to the beaker while    mixing.-   3. The pH was adjusted to 7.35 using 1N Sodium Hydroxide or 1N    Hydrochloric Acid.-   4. While mixing, 0.015 grams of a solution of 33% Polyquaternium 42    was added to the beaker.-   5. Finally, 0.35 grams of Sodium Citrate Dihydrate was added and mix    until dissolved.

The procedure for preparing the Solution 6B was as follows:

-   1. Into a beaker was poured 99 grams of a 0.2% Sodium Hyaluronate    solution as prepared in Step 1 of the preparation of Solution 6A.-   2. Next, 0.35 grams of Sodium Citrate Dihydrate was added and mix    until dissolved.-   3. The pH was measured to be 7.6.-   4. While mixing, 0.015 grams of a solution of 33% Polyquaternium 42    was added to the beaker.

Both solutions containing the sodium citrate, dihydate or the sodiumcitrate, dihydrate/citric acid combination, in each case, as the organicacid were clear. The sodium citrate, dihydrate and citric acid used inthis example had solubilities from Table 1 of about 77 g and 59.2 g/100ml of water (at 25° C.), respectively—or solubilities greater than the10 g/100 ml threshold solubility (at 25° C.) for organic acids useful inthe present invention.

Example 7: Solution with Anionic Polymer and Polyquaternium

A solution was prepared containing both and anionic polymer (SodiumHyaluronate) and a Polyquaternium (PQ42). Table 8 shows the list ofingredients.

TABLE 8 Example 7 components. 7 amount per INGREDIENT % w/w batch (gms)Sodium Hyaluronate 0.200 0.200 Polyquaternium 42 0.005 0.005 L-TartaricAcid 5.0 5.0 Purified Water 94.785 94.785 total 100.00% 100.000

The Sodium Hyaluronate was supplied by LIFECORE (CHASKA, Minn.). ThePolyquaternium 42 was supplied as Polyquaternium 42 (33% aqueous) by DSMBIOMEDICAL (BERKELEY, Calif.). The L-Tartaric Acid was supplied byAMRESCO (SOLON, Ohio).

The procedure for preparing the Solution 7 was as follows:

-   1. Into a beaker was poured 50 grams of a 0.4% Sodium Hyaluronate    solution which was prepared by adding 2958 grams of water into a    separate container and slowly adding 12 grams of Sodium Hyaluronate    into the water. The solution was mixed for 3 hours at ambient    temperature to disperse the Sodium Hyaluronate. Additional water was    added to bring the total amount of the solution to 3000 grams and    mixing the solution an additional 10 minutes.-   2. To the above 50 grams of 0.4% Sodium Hyaluronate solution was    added 44 grams of water and the solution was mixed for 5 minutes to    disperse the polymer uniformly.-   3. While continuing to mix, 5 grams of L-Tartaric acid was added to    the above solution.

The solution was mixed an additional 5 minutes.

-   4. The above quantity of Polyquaternium 42, supplied as: 0.0015    grams of 33% Polyquaternium 42 was next added to the solution.-   5. The solution was q.s.ed to 100 grams and mixed an additional 5    minutes.

The solution containing the L-tartaric acid as the organic acid wasclear throughout the addition of the Polyquaternium 42 and remainedclear. The L-tartaric acid used in this example had a solubility fromTable 1 of >100 g/100 ml of water (at 25° C.)—or a solubility greaterthan the 10 g/100 ml threshold solubility (at 25° C.) for organic acidsuseful in the present invention.

Example 8: Solution with Anionic Polymer and Polyquaternium

A solution was prepared containing both and anionic polymer (SodiumHyaluronate) and a Polyquaternium (PQ42). Table 9 shows the list ofingredients.

TABLE 9 Example 8 components. amount per INGREDIENT % w/w batch (gms)Gantrez S-95 0.500 0.250 Polyquaternium 42 0.003 0.0015 Sodium Citrate,0.70 0.35 Dihydrate Purified Water 98.797 49.3985 total 100.00% 50.000

The Gantrez S-95 was supplied by ASHLAND (WILMINGTON, Del.). ThePolyquaternium 42 was supplied as Polyquaternium 42 (33% aqueous) by DSMBIOMEDICAL, (BERKELEY, Calif.). The sodium citrate, dihydrate wastri-Sodium Citrate supplied by MERCK (DARMSTADT, GERMANY).

The procedure for preparing the Solution 8 was as follows:

-   1. Into a beaker was poured 48.93 grams of Purified Water USP. .-   2. To the above was added 0.715 grams of Gantrez S-95 supplied as    35% aqueous solution while mixing to disperse.-   3. To the above was added 0.0045 grams of Polyquaternium 42 (33%    aqueous).-   4. To the above cloudy dispersion was added 0.35 grams of Sodium    Citrate Dihydrate while mixing.

The solution was cloudy prior to the addition of the Sodium Citrate,Dihydrate. Upon addition of the Sodium Citrate Dihydrate, the solutionbecame clear. The sodium citrate, dehydrate used in this example as theorganic acid had a solubility from Table 1 of about 77 g/100 ml of water(at 25° C.)—or a solubility greater than the 10 g/100 ml thresholdsolubility (at 25° C.) for organic acids useful in the presentinvention.

Example 9: Solution with Anionic Polymer and Polyquaternium

Solutions were prepared containing both and anionic polymer (SodiumHyaluronate or Gantrez S-96) and a Polyquaternium (PQ42 or PQ10). Table10 shows the list of ingredients for solutions 9A-9D.

TABLE 10 Example 9 components. 9A 9B 9C 9D amount amount amount amountper per per per batch batch batch batch INGREDIENT % w/w (gms) % w/w(gms) % w/w (gms) % w/w (gms) Sodium 0.2 0.2 — — 0.2 0.2 — — HyaluronateGantrez S-96 — — 0.5 0.5 — — 0.5 0.5 Polyquaternium — — — — 0.1 0.1 0.10.1 10 Polyquaternium 0.005 0.005 0.005 0.005 — — — — 42 Maleic Acid38.0 38.0 38.0 38.0 38.0 38.0 38.0 38.0 Purified Water 61.795 61.79561.495 61.495 61.7 61.7 61.4 61.4 total 100.00% 100.00 g 100.00% 100.00g 100.00% 100.00 g 100.00% 100.00 g

The sodium hyaluronate was supplied by LIFECORE (CHASKA, Minn.). TheGantrez S-96 was supplied by ASHLAND (WILMINGTON, Del.). Polyquaternium42 was supplied as Polyquaternium 42 (33% aqueous) by DSM BIOMEDICAL,(BERKELEY, Calif.). Polyquaternium 10 was supplied by ALDRICH CHEMICALS(ST. LOUIS, Mo.). The maleic acid was supplied by ALFA AESAR (HEYSHAM,ENGLAND).

The procedure for preparing Solutions 9A and 9C was as follows:

-   1. Into a beaker was poured 100.00 grams of a 0.4% Sodium    Hyaluronate Solution which was prepared by adding 2988 grams of    water into a separate container and slowly adding 12 gram of Sodium    Hyaluronate into the water. The solution was mixed for 2 hours at    ambient temperature to disperse the Sodium Hyaluronate. Additional    water was added to bring the total amount of the solution to 166    grams and mixing the solution an additional 10 minutes.-   2. Next, 20 grams of Purified Water USP was added to the beaker    while mixing to disperse and solubilize.-   3. Next, 76 grams of Maleic acid was added and mixed. The    temperature of the resulting cold undissolved mixture was 11.9° C.    and the solution was heated to 25° C. to thoroughly dissolve the    acid.-   4. Half of the above solution was separated for use as described in    step. 7.-   5. A total of 0.015 gram of Polyquaternium 42 was added to the    remaining half of solution of step 4 while mixing.-   6. The solution was brought to 100 g using purified water and mixed    for 5 minutes.-   7. To the separated solution from step 4 was added 0.10 gram of    Polyquaternium 10 while mixing.-   8. The solution prepared in step 7 was brought to 100 g using    purified water and mixed for 10 minutes.

The procedure for preparing Solutions 9B and 9D was as follows:

-   1. Into a beaker containing 110.00 grams of water was slowly added    7.7 gram of a 13% solution of Gantrez S-96 as supplied.-   2. The solution was mixed for 5 minutes to uniformly dissolve the    Gantrez S-96.-   3. To the above was added 76.0 grams of Maleic acid resulting in a    cold undissolved mixture at a temperature of 10.7° C.-   4. The solution was heated to 25° C. and mixed to dissolve.-   5. Half of the above solution was separated for use as described in    step 8.-   6. To the remaining solution in step 5 was added 0.015 gram of    Polyquaternium 42 while mixing.-   7. The solution was brought to 100 g using purified water and mixed    for 10 minutes.-   8. To the separated solution from step 5 was added 0.10 gram of    Polyquaternium 10 while mixing.-   9. The solution in step 8 was brought to 100 g using purified water    and mixed for 10 minutes.

Solutions 9A, 9B, 9C, and 9D containing maleic acid as the organic acidwere clear and colorless with no precipitation evident. The maleic acidused in this example had a solubility from Table 1 of 78 g/100 ml ofwater (at 25° C.)—or a solubility greater than the 10 g/100 ml thresholdsolubility (at 25° C.) for organic acids useful in the presentinvention.

Example 10: Solution with Anionic Polymer and Polyquaternium

Solutions were prepared containing both and anionic polymer (SodiumHyaluronate or Gantrez S-96) and a Polyquaternium (PQ42 or PQ10). Table11 shows the list of ingredients for solutions 10A-10D.

TABLE 11 Example 10 components. 10A 10B 10C 10D amount amount amountamount per per per per batch batch batch batch INGREDIENT % w/w (gms) %w/w (gms) % w/w (gms) % w/w (gms) Sodium 0.2 0.2 — — 0.2 0.2 — —Hyaluronate Gantrez S-96 — — 0.5 0.5 — — 0.5 0.5 Polyquaternium — — — —0.01 0.01 0.01 0.01 10 Polyquaternium 0.005 0.005 0.005 0.005 — — — — 42L-Tartaric 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Acid Purified Water 94.79594.795 94.495 94.495 94.79 94.79 94.49 94.49 total 100.00% 100.00 g100.00% 100.00 g 100.00% 100.00 g 100.00% 100.00 g

The sodium hyaluronate was supplied by LIFECORE (CHASKA, Minn.). TheGantrez S-96 was supplied by ASHLAND (WILMINGTON, Del.). Polyquaternium42 was supplied as Polyquaternium 42 (33% aqueous) by DSM BIOMEDICAL,(BERKELEY, Calif.). Polyquaternium 10 was supplied by ALDRICH CHEMICALS(ST. LOUIS, Mo.). The tartaric acid was supplied by AMRESCO (SOLON,Ohio).

The procedure for preparing Solutions 10A and 10C was as follows:

-   1. To each of 2 beakers was poured 50.00 grams of a 0.4% Sodium    Hyaluronate Solution which was prepared by adding 249 grams of water    into a separate container and slowly adding 1 gram of Sodium    Hyaluronate into the water. The solution was mixed for 2 hours at    ambient temperature to disperse the Sodium Hyaluronate. Additional    water was added to bring the total amount of the solution to 94    grams and the solution is mixed an additional 10 minutes.-   2. To each beaker solution was added 5 grams of Tartaric acid and    mixed for 5 minutes to thoroughly dissolve the acid.-   3. A total of 0.015 gram of Polyquaternium 42 is added to the    solution of one of the beakers above while mixing.-   4. The solution of step 3 is brought to 100 g using purified water    and mixed for 5 minutes.-   5. To the solution in the remaining beaker was added 0.01 gram of    Polyquaternium 10 while mixing.-   6. The solution prepared in step 5 was brought to 100 g using    purified water and mixed for 10 minutes.

The procedure for preparing Solutions 10B and 10D was as follows:

-   1. Into a beaker containing 110.00 grams of water was slowly added    7.7 gram of a 13% solution of Gantrez S-96 as supplied.-   2. The solution was mixed for 5 minutes to uniformly dissolve.-   3. To the solution of step 2 was added 10.0 grams of Tartaric acid    and mixed to dissolve.-   4. Half of the solution of step 3 was separated for use as described    in step 10.-   5. To the remaining solution of step 3 was added 0.015 grams of    Polyquaternium 42 while mixing.-   9. The solution in step 5 was brought to 100 g using purified water    and mixed for 5 minutes.-   10. To the separated solution of step 4 was added 0.01 gram of    Polyquaternium 10 while mixing.-   11. The solution was brought to 100 g using purified water and mixed    for 10 minutes.

Solutions 10A, 10B, 10C, and 10D containing the L-tartaric acid as theorganic acid are clear and colorless with no precipitation evident. TheL-tartaric acid used in this example had a solubility from Table 1of >100 g/100 ml of water (at 25° C.)—or a solubility greater than the10 g/100 ml threshold solubility (at 25° C.) for organic acids useful inthe present invention.

Example 11: Solution with Anionic Polymer and Polyquaternium

Solutions were prepared containing both and anionic polymer (SodiumHyaluronate or Gantrez S-96) and a Polyquaternium (PQ42 or PQ10). Table12 shows the list of ingredients for solutions 11A-11D.

TABLE 12 Example 11 components. 11A 11B 11C 11D amount amount amountamount per per per per batch batch batch batch INGREDIENT % w/w (gms) %w/w (gms) % w/w (gms) % w/w (gms) Sodium 0.200 0.200 — — 0.200 0.200 — —Hyaluronate Gantrez S-96 — — 0.5 0.5 — — 0.5 0.5 Polyquaternium 0.1 0.1— — 0.1 0.1 — — 10 Polyquaternium — — 0.005 0.005 — — 0.005 0.005 42Acetic Acid 45.0 45.0 45.0 45.0 — — — — Glutaric Acid — — — 32.0 32.032.0 32.0 Purified Water 54.7 54.7 54.495 54.495 67.7 67.7 67.495 67.495total 100.00% 100.00 g 100.00% 100.00 g 100.00% 100.00 g 100.00% 250.00g

The sodium hyaluronate was supplied by LIFECORE (CHASKA, Minn.). TheGantrez S-96 was supplied by ASHLAND (WILMINGTON, Del.). Polyquaternium42 was supplied as Polyquaternium 42 (33% aqueous) by DSM BIOMEDICAL,(BERKELEY, Calif.). Polyquaternium 10 was supplied by ALDRICH CHEMICALS(ST. LOUIS, Mo.). The acetic acid was supplied by AVANTOR (PHILLIPSBURG,N.J.). The glutaric acid was supplied by ALFA AESAR (WARD HILL, Mass.).

The procedure for preparing Solutions 11A was as follows:

-   1. Into a beaker was poured 50.00 grams of a 0.4% Sodium Hyaluronate    Solution which was prepared by adding 2988 grams of water into a    separate container and slowly adding 12 gram of Sodium Hyaluronate    into the water. The solution was mixed for 2 hours at ambient    temperature to disperse the Sodium Hyaluronate.-   2. Next, 45 grams of acetic acid was added to the beaker while    mixing to disperse and solubilize.-   3. Next, 0.10 gram of Polyquaternium 10 was added and mixed for 5    minutes to dissolve.-   4. The solution prepared in step 3 was brought to 100 g using    purified water and mixed for 10 minutes.

The procedure for preparing Solutions 11C was as follows:

-   1. Into a beaker was poured 100.00 grams of a 0.4% Sodium    Hyaluronate Solution which was prepared by adding 2988 grams of    water into a separate container and slowly adding 12 gram of Sodium    Hyaluronate into the water. The solution was mixed for 2 hours at    ambient temperature to disperse the Sodium Hyaluronate.-   2. Next, 64 grams of glutaric acid was added to the beaker while    mixing to disperse and solubilize.-   3. The temperature of the solution was 10.1° C. (due to the    endothermic reaction in step 2) and the solution was heated to    25° C. while mixing.-   4. To half of the solution in step 3 was added 0.10 gram of    Polyquaternium 10.-   5. The solution was brought to a weight of 100 grams using purified    water and mixed for 10 minutes.

The procedure for preparing Solutions 11B was as follows:

-   1. Into a beaker containing 46.15 grams of water was slowly added    3.85 gram of a 13% solution of Gantrez S-96 as supplied.-   2. The solution was mixed for 5 minutes to dissolve.-   3. To the solution of step 2 was added 45.0 grams of acetic acid    while mixing.-   4. To the solution of step 3 was added 0.015 grams of    polyquaternium-42 while mixing.-   5. The solution of step 4 was brought to 100 grams using purified    water and mixed for 10 minutes.

The procedure for preparing Solutions 11D was as follows:

-   1. Into a beaker containing 110.00 grams of purified water was    slowly added 7.7 gram of a 13% solution of Gantrez S-96 as supplied.-   2. The solution was mixed for 5 minutes to uniformly dissolve.-   3. To the solution of step 2 was added 64.0 grams of glutaric acid    resulting in a cold undissolved mixture at a temperature of 20° C.-   4. The solution was heated to 25° C. and mixed to dissolve.-   5. Half of the above solution is removed.-   6. To the remaining solution of step 4 was added 0.015 grams of    Polyquaternium-42 while mixing to dissolve.-   7. The solution was brought to 100 grams using purified water and    mixed 10 minutes to dissolve.

Solutions 11A, 11B, 11C, and 11D containing either the glutaric oracetic acids as the organic acid are clear and colorless with noprecipitation evident. The glutaric or acetic acids used in this examplehad solubilities from Table 1 of 63.9 and >100 g/100 ml of water (at 25°C.), respectively—or solubilities greater than the 10 g/100 ml thresholdsolubility (at 25° C.) for organic acids useful in the presentinvention.

Example 12: Solution with Anionic Polymer and Polyquaternium

Solutions were prepared containing both and anionic polymer (SodiumHyaluronate or Gantrez S-96) and a Polyquaternium (PQ42 or PQ10). Table13 shows the list of ingredients for solutions 12A-12D.

TABLE 13 Example 12 components. 12A 12B 12C 12D amount amount amountamount per per per per batch batch batch batch INGREDIENT % w/w (gms) %w/w (gms) % w/w (gms) % w/w (gms) Sodium 0.2 0.2 — — 0.2 0.2 — —Hyaluronate Gantrez S-96 — — 0.5 0.5 — — 0.5 0.5 Polyquaternium — — — —0.01 0.01 — — 10 Polyquaternium 0.005 0.0005 0.01 0.01 — — 0.005 0.00542 Citric Acid 30.0 30.0 15.0 15.0 20.0 20.0 15.0 15.0 Purified Water69.795 69.795 84.49 84.49 79.79 79.79 84.495 84.495 total 100.00% 100.00g 100.00% 100.00 g 100.00% 100.00 g 100.00% 100.00 g

The sodium hyaluronate was supplied by LIFECORE (CHASKA, Minn.). TheGantrez S-96 was supplied by ASHLAND (WILMINGTON, Del.). Polyquaternium42 was supplied as Polyquaternium 42 (33% aqueous) by DSM BIOMEDICAL,(BERKELEY, Calif.). Polyquaternium 10 was supplied by ALDRICH CHEMICALS(ST. LOUIS, Mo.). The citric acid anhydrous was supplied by VWR/BDH(WEST CHESTER, Pa.).

The procedure for preparing Solutions 12A and 12C was as follows:

-   1. To each of 2 beakers was poured 50.00 grams of a 0.4% Sodium    Hyaluronate Solution which was previously prepared by adding 249    grams of purified water into a separate container and slowly adding    1 gram of Sodium Hyaluronate into the water and mixed for 2 hours at    ambient temperature to disperse the Sodium Hyaluronate.-   2. To the solution of one of the beakers of was added 30 grams of    citric acid and mixed thoroughly to dissolve the acid.-   3. A total of 0.015 gram of Polyquaternium 42 was added to the    solution in step 2 above while mixing.-   4. The solution of step 3 was brought to 100 g using purified water    and mixed for 5 minutes.-   5. To the solution of the remaining beaker was added 20 grams of    citric acid and mixed thoroughly to dissolve the acid.-   6. To the solution of step 5 was added 0.01 gram of Polyquaternium    10 while mixing.-   7. The solution prepared in step 6 was brought to 100 g using    purified water and mixed for 10 minutes.

The procedure for preparing Solutions 12B and 12D was as follows:

-   1. Into each of two beakers containing 70.00 grams of water was    slowly added 3.85 gram of a 13% solution of Gantrez S-96 as    supplied.-   2. The solutions were mixed for 5 minutes to uniformly dissolve.-   3. To each of the 2 beakers was added 15.0 grams of citric acid and,    in each case, mixed to dissolve.-   4. To solution of one of the beakers from step 3 was added 0.015    grams of Polyquaternium 42 while mixing.-   5. The solution was brought to 100 g using purified water and mixed    for 5 minutes.-   6. To the solution of the remaining beaker from step 3 was added    0.01 gram of Polyquaternium 10 while mixing.-   7. The solution was brought to 100 g using purified water and mixed    for 10 minutes.

Solutions 12A, 12B, 12C, and 12D containing citric acid as the organicacid are clear and colorless with no precipitation evident. The citricacid used in this example had a solubility from Table 1 of 59.2 g/100 mlof water (at 25° C.)—or a solubility greater than the 10 g/100 mlthreshold solubility (at 25° C.) for organic acids useful in the presentinvention.

Example 13: Solution with Anionic Polymer and Polyquaternium

Solutions were prepared containing both and anionic polymer (SodiumHyaluronate or Gantrez S-96) and a Polyquaternium (PQ42 or PQ10). Table14 shows the list of ingredients for solutions 13A-13D.

TABLE 14 Example 13 components. 13A 13B 13C 13D amount amount amountamount per per per per batch batch batch batch INGREDIENT % w/w (gms) %w/w (gms) % w/w (gms) % w/w (gms) Sodium 0.2 0.2 — — 0.2 0.2 — —Hyaluronate Gantrez S-96 — — 0.5 0.5 — — 0.5 0.5 Polyquaternium 0.010.01 0.01 0.01 — — 10 Polyquaternium — — — — 0.005 0.005 0.005 0.005 42Succinic Acid 4.0 4.0 3.0 3.0 3.0 3.0 4.0 4.0 Purified Water 95.79 95.7996.49 96.49 96.795 96.795 95.495 95.495 total 100.00% 100.00 g 100.00%100.00 g 100.00% 100.00 g 100.00% 100.00 g

The sodium hyaluronate was supplied by LIFECORE (CHASKA, Minn.). TheGantrez S-96 was supplied by ASHLAND (WILMINGTON, Del.). Polyquaternium42 was supplied as Polyquaternium 42 (33% aqueous) by DSM BIOMEDICAL,(BERKELEY, Calif.). Polyquaternium 10 was supplied by ALDRICH CHEMICALS(ST. LOUIS, Mo.). The succinic acid was supplied by AI RESCO (SOLON,Ohio).

The procedure for preparing Solutions 13A and 13C was as follows:

-   1. To each of 2 beakers was poured 50.00 grams of a 0.4% Sodium    Hyaluronate Solution which was previously prepared by adding 249    grams of purified water into a separate container and slowly adding    1 gram of Sodium Hyaluronate into the water and mixing for 2 hours    at ambient temperature to disperse the Sodium Hyaluronate.-   2. To the solution of one of the beakers was added 3 grams of    succinic acid and mixed thoroughly to dissolve the acid.-   3. A total of 0.015 gram of Polyquaternium 42 was added to the    solution in step 2 above while mixing.-   4. The solution was brought to 100 g using purified water and mixed    for 5 minutes.-   5. To the solution in the remaining beaker from step 1 was added 4    grams of succinic acid which is mixed thoroughly to dissolve the    acid.-   6. To the solution of step 5 was added 0.01 gram of Polyquaternium    10 while mixing.-   7. The solution prepared in step 6 was brought to 100 g using    purified water and mixed for 10 minutes.

The procedure for preparing Solutions 13B and 13D was as follows:

-   1. Into each of two beakers containing 86.15 grams of purified water    was slowly added 3.85 gram of a 13% solution of Gantrez S-96 as    supplied.-   2. The each solution of step 1 was mixed for 5 minutes to uniformly    dissolve.-   3. To the solution of one of the beakers of step 2 was added 4.0    grams of succinic acid which is mixed to dissolve.-   4. To the above solution in step 3 was added 0.015 grams of    Polyquaternium 42 while mixing.-   5. The solution of step 4 was brought to 100 g using purified water    and mixed for 5 minutes.-   6. To the solution of the remaining beaker from step 2 was added    0.01 gram of Polyquaternium 10 while mixing.-   7. The solution of step 6 was brought to 100 g using purified water    and mixed for 10 minutes.

Solutions 13A, 13B, 13C, and 13D containing the succinic acid as theorganic acid are visually observed and noted to have precipitation. Thesuccinic acid used in this example had a solubility from Table 1 of 8g/100 ml of water (at 25° C.)—or a solubility less than the 10 g/100 mlthreshold solubility (at 25° C.) for organic acids useful in the presentinvention.

1-20. (canceled)
 21. A method of reducing, inhibiting or preventing theprecipitation of a polyquaternium compound and an anionic polymer in acomposition comprising such compounds, comprising the steps of: i)providing from about 0.001% to about 0.5% of an anionic polymer having aweight average molecular weight of from about 250 to about 4,000,000Daltons; ii) adding an effective amount of an organic acid, saltsthereof or mixtures thereof, such that the organic acid binds with themonomer units of the polyquaternium compound at at least a 1:1 molarratio; and iii) adding from about 10 ppm to about 1000 ppm of apolyquaternium compound having a weight average molecular weight of fromabout 150 to about 15,000 Daltons; wherein the composition issubstantially free of cationic oligomer compounds and precipitationinhibiting compounds.